NF-κB inhibitor on Toll-like receptor 4 signal-induced expression of angiotensinogen and AT1a receptor in neonatal rat left ventricular myocytes

Abstract Background/Introduction Mitochondria are dynamic regulators of cellular metabolism and homeostasis. The dysfunction of mitochondria has long been considered a major contributor to aging and age-related diseases. The prognosis of severe heart failure is still unacceptably poor and it is urgent to establish new therapies for this critical condition. Some patients with heart failure do not respond to established multidisciplinary treatment and they are classified as “non-responders”. The outcome is especially poor for non-responders, and underlying mechanisms are largely unknown. Purpose Studies indicate mitochondrial dysfunction has causal roles for metabolic remodeling in the failing heart, but underlying mechanisms remain to be explored. This study tried to elucidate the role of Mitofusin-1 in a failing heart. Methods We examined twenty-two heart failure patients who underwent endomyocardial biopsy of intraventricular septum. Patients were classified as non-responders when their left-ventricular (LV) ejection fraction did not show more than 10% improvement at remote phase after biopsy. Fourteen patients were classified as responders, and eight as non-responders. Electron microscopy, quantitative PCR, and immunofluorescence studies were performed to explore the biological processes or molecules involved in failure to respond. In addition to studies with cardiac tissue specific knockout mice, we also conducted functional in-vitro studies with neonatal rat ventricular myocytes. Results Twenty-two patients with IDCM who underwent endomyocardial biopsy were enrolled in this study, including 14 responders and 8 non-responders. Transmission electron microscopy (EM) showed a significant reduction in mitochondrial size in cardiomyocytes of non-responders compared to responders. Quantitative PCR revealed that transcript of mitochondrial fusion protein, Mitofusin-1, was significantly reduced in non-responders. Studies with neonatal rat ventricular myocytes (NRVMs) indicated that the beta-1 adrenergic receptor-mediated signaling pathway negatively regulates Mitofusin-1 expression. Suppression of Mitofusin-1 resulted in a significant reduction in mitochondrial respiration of NRVMs. We generated left ventricular pressure overload model with thoracic aortic constriction (TAC) in cardiac specific Mitofusin-1 knockout model (c-Mfn1 KO). Systolic function was reduced in c-Mfn1 KO mice, and EM study showed an increase in dysfunctional mitochondria in the KO group subjected to TAC. Conclusions Mitofusin-1 becomes a biomarker for non-responders with heart failure. In addition, our results suggest that therapies targeting mitochondrial dynamics and homeostasis would become next generation therapy for severe heart failure patients. Funding Acknowledgement Type of funding source: None

Download Full-text

Myocarditis-associated necrotizing coronary vasculitis: incidence, cause, and outcome

European Heart Journal ◽

10.1093/eurheartj/ehaa973 ◽

2020 ◽

Author(s):

Andrea Frustaci ◽

Maria Alfarano ◽

Romina Verardo ◽

Chiara Agrati ◽

Rita Casetti ◽

...

Keyword(s):

Hospital Mortality ◽

Hypereosinophilic Syndrome ◽

Left Ventricular ◽

Response To Therapy ◽

Left Ventricular Ejection ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Ventricular Ejection Fraction ◽

Immune Mediated ◽

Coronary Vasculitis

Abstract Aims Necrotizing coronary vasculitis (NCV) is a rare entity usually associated to myocarditis which incidence, cause, and response to therapy is unreported. Methods and results Among 1916 patients with biopsy-proven myocarditis, 30 had NCV. Endomyocardial samples were retrospectively investigated with immunohistochemistry for toll-like receptor 4 (TLR4) and real-time polymerase chain reaction (PCR) for viral genomes. Serum samples were processed for anti-heart autoantibodies (Abs), IL-1β, IL-6, IL-8, tumour necrosis factor (TNF)-α. Identification of an immunologic pathway (including virus-negativity, TLR4-, and Ab-positivity) was followed by immunosuppression. Myocarditis-NCV cohort was followed for 6 months with 2D-echo and/or cardiac magnetic resonance and compared with 60 Myocarditis patients and 30 controls. Increase in left ventricular ejection fraction ≥10% was classified as response to therapy. Control endomyocardial biopsy followed the end of treatment. Twenty-six Myocarditis-NCV patients presented with heart failure; four with electrical instability. Cause of Myocarditis-NCV included infectious agents (10%) and immune-mediated causes (chest trauma 3%; drug hypersensitivity 7%; hypereosinophilic syndrome 3%; primary autoimmune diseases 33%, idiopathic 44%). Abs were positive in immune-mediated Myocarditis-NCV and virus-negative Myocarditis; Myocarditis-NCV patients with Ab+ presented autoreactivity in vessel walls. Toll-like receptor 4 was overexpressed in immune-mediated forms and poorly detectable in viral. Interleukin-1β was significantly higher in Myocarditis-NCV than Myocarditis, the former presenting 24% in-hospital mortality compared with 1.5% of Myocarditis cohort. Immunosuppression induced improvement of cardiac function in 88% of Myocarditis-NCV and 86% of virus-negative Myocarditis patients. Conclusion Necrotizing coronary vasculitis is histologically detectable in 1.5% of Myocarditis. Necrotizing coronary vasculitis includes viral and immune-mediated causes. Intra-hospital mortality is 24%. The immunologic pathway is associated with beneficial response to immunosuppression.

Download Full-text

Partially Silencing Brain Toll-Like Receptor 4 Prevents in Part Left Ventricular Remodeling with Sympathoinhibition in Rats with Myocardial Infarction-Induced Heart Failure

PLoS ONE ◽

10.1371/journal.pone.0069053 ◽

2013 ◽

Vol 8 (7) ◽

pp. e69053 ◽

Cited By ~ 9

Author(s):

Kiyohiro Ogawa ◽

Yoshitaka Hirooka ◽

Takuya Kishi ◽

Tomomi Ide ◽

Kenji Sunagawa

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Ventricular Remodeling ◽

Left Ventricular Remodeling ◽

Left Ventricular ◽

Toll Like Receptor ◽

Toll Like Receptor 4

Download Full-text

Abstract 631 ADAM12 Is An Important Regulator Of Myocyte Apoptosis Induced By β-adrenergic Receptor Stimulation

Circulation ◽

10.1161/circ.116.suppl_16.ii_115-c ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Hang Xi ◽

Khadija Rafiq ◽

Marie Hanscom ◽

Rachid Seqqat ◽

Nikolay L Malinin ◽

...

Keyword(s):

Ventricular Myocytes ◽

Left Ventricular ◽

Surface Proteins ◽

Neonatal Rat ◽

Human Heart Failure ◽

Activation Mechanisms ◽

Myocyte Apoptosis ◽

Protease Deficient

ADAM (A Disintegrin And Metalloprotease)12 is a member of a family of cell surface proteins with protease and cell-binding activities. Recent work showed ADAM12 up-regulation in human heart failure. However, the activation mechanisms of ADAM12 in the heart are obscure. We hypothesized that β-adrenergic receptors (AR) stimulation regulates ADAM12 activation in neonatal rat ventricular myocytes (NRVMs) in-vitro and after injection of isoproterenol (ISO) in-vivo. Wistar rats received a single injection of ISO (5 mg/kg) and were sacrificed 6, 24 and 72 hrs later. In comparison with controls, left ventricular function was impaired in rats 24 hrs after ISO injection and started to improve at 72 hrs. The fraction of myocytes undergoing apoptosis peaked 24 hrs after ISO injection and declined thereafter. ADAM12 protein was reduced in hearts from ISO treated animals at 6 hrs, pointing to a possible increase in ADAM12 proteolytic activity. However, both ADAM12 expression and activation were significantly up-regulated at 24 and 72 hrs after ISO injection. We therefore assessed whether ADAM12 activation was involved in myocyte apoptosis secondary to excess exposure of catecholamine. Acute stimulation with ISO (10 μM, 30 min to 3 hrs) induced accumulation of ADAM12 N-terminal cleavage product in conditioned medium, demonstrating activation of the ADAM metalloprotease activity. However, chronic stimulation with ISO for 24 hrs and 48 hrs significantly increased both ADAM12 expression and secretion. This ISO-induced ADAM12 expression/activation was mediated through β 1 -AR stimulation and was dependent on intracellular calcium elevation and protein kinase C activation. Adenoviral expression of an ADAM12 protease-deficient mutant (ADAM12DeltaMP) blocks β-AR-induced myocyte apoptosis, while transduction of NRVMs with adenovirus harboring ADAM12 significantly increased myocyte apoptosis. These data suggest that ADAM12 is a regulator of myocyte apoptosis induced by β-AR in NRVMs and may play an important autocrine role in mediating the effects of β-AR on myocardial remodeling.

Download Full-text

TLR (Toll-Like Receptor) 4 Antagonism Prevents Left Ventricular Hypertrophy and Dysfunction Caused by Neonatal Hyperoxia Exposure in Rats

Hypertension ◽

10.1161/hypertensionaha.119.13022 ◽

2019 ◽

Vol 74 (4) ◽

pp. 843-853 ◽

Cited By ~ 7

Author(s):

Muhammad Oneeb Rehman Mian ◽

Ying He ◽

Mariane Bertagnolli ◽

Thuy-An Mai-Vo ◽

Rafael Oliveira Fernandes ◽

...

Keyword(s):

Left Ventricular Hypertrophy ◽

Ventricular Hypertrophy ◽

Left Ventricular ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Hyperoxia Exposure ◽

Neonatal Hyperoxia

Download Full-text

Signaling for myocardial depression in hemorrhagic shock: roles of Toll-like receptor 4 and p55 TNF-α receptor

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00182.2004 ◽

2005 ◽

Vol 288 (3) ◽

pp. R600-R606 ◽

Cited By ~ 35

Author(s):

Xianzhong Meng ◽

Lihua Ao ◽

Yong Song ◽

Christopher D. Raeburn ◽

David A. Fullerton ◽

...

Keyword(s):

Hemorrhagic Shock ◽

Gene Knockout ◽

Left Ventricular ◽

Toll Like Receptor ◽

Myocardial Depression ◽

Toll Like Receptor 4 ◽

Proinflammatory Mediators ◽

Cellular Expression ◽

Tnf Α ◽

Myocardial Contractile

Hemorrhagic shock causes myocardial contractile depression. Although this myocardial disorder is associated with increased expression of tumor necrosis factor-α (TNF-α), the role of TNF-α as a myocardial depressant factor in hemorrhagic shock remains to be determined. Moreover, it is unclear which TNF-α receptor mediates the myocardial depressive effects of TNF-α. Toll-like receptor 4 (TLR4) regulates cellular expression of proinflammatory mediators following lipopolysaccharide stimulation and may be involved in the tissue inflammatory response to injury. The contribution of TLR4 signaling to tissue TNF-α response to hemorrhagic shock and TLR4’s role in myocardial depression during hemorrhagic shock are presently unknown. We examined the relationship of TNF-α production to myocardial depression in a mouse model of nonresuscitated hemorrhagic shock, assessed the influence of TLR4 mutation, resulting in defective signaling, on TNF-α production and myocardial depression, and determined the roles of TNF-α and TNF-α receptors in myocardial depression using a gene knockout (KO) approach. Hemorrhagic shock resulted in increased plasma and myocardial TNF-α (4.9- and 4.5-fold, respectively) at 30 min and induced myocardial contractile depression at 4 h. TLR4 mutation abolished the TNF-α response and attenuated myocardial depression (left ventricular developed pressure of 43.0 ± 6.2 mmHg in TLR4 mutant vs. 30.0 ± 3.6 mmHg in wild type, P < 0.05). TNF-α KO also attenuated myocardial depression in hemorrhagic shock, and the p55 receptor KO, but not the p75 receptor KO, mimicked the effect of TNF-α KO. The results suggest that TLR4 plays a novel role in signaling to the TNF-α response during hemorrhagic shock and that TNF-α through the p55 receptor activates a pathway leading to myocardial depression. Thus TLR4 and the p55 TNF-α receptor represent therapeutic targets for preservation of cardiac mechanical function during hemorrhagic shock.

Download Full-text